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Article: Editorial: Understanding retinal remodeling: Retinal alterations and therapeutic implications.

García-Ayuso, Diego / Esquiva, Gema / Hombrebueno, Jose R

2023 Volume 17, Page(s) 1191906

Language	English
Publishing date	2023-04-05
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2452969-2
ISSN	1662-5129
ISSN	1662-5129
DOI	10.3389/fnana.2023.1191906
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Article ; Online: Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status.

Anderson, Aidan / Alfahad, Nada / Wimalachandra, Dulani / Bouzinab, Kaouthar / Rudzinska, Paula / Wood, Heather / Fazey, Isabel / Xu, Heping / Lyons, Timothy J / Barnes, Nicholas M / Narendran, Parth / Lord, Janet M / Rauz, Saaeha / Ganley, Ian G / Curtis, Tim M / Wallace, Graham R / Hombrebueno, Jose R

Nature communications

2024 Volume 15, Issue 1, Page(s) 1124

Abstract: The recovery of mitochondrial quality control (MQC) may bring innovative solutions for neuroprotection, while imposing a significant challenge given the need of holistic approaches to restore mitochondrial dynamics (fusion/fission) and turnover ( ... ...

Abstract	The recovery of mitochondrial quality control (MQC) may bring innovative solutions for neuroprotection, while imposing a significant challenge given the need of holistic approaches to restore mitochondrial dynamics (fusion/fission) and turnover (mitophagy and biogenesis). In diabetic retinopathy, this is compounded by our lack of understanding of human retinal neurodegeneration, but also how MQC processes interact during disease progression. Here, we show that mitochondria hyperfusion is characteristic of retinal neurodegeneration in human and murine diabetes, blunting the homeostatic turnover of mitochondria and causing metabolic and neuro-inflammatory stress. By mimicking this mitochondrial remodelling in vitro, we ascertain that N6-furfuryladenosine enhances mitochondrial turnover and bioenergetics by relaxing hyperfusion in a controlled fashion. Oral administration of N6-furfuryladenosine enhances mitochondrial turnover in the diabetic mouse retina (Ins2
MeSH term(s)	Male ; Mice ; Humans ; Animals ; Mitochondrial Dynamics ; Neuroprotection ; Diabetes Mellitus, Experimental/metabolism ; Retina/metabolism ; Mitochondria/metabolism ; Adenosine ; Kinetin
Chemical Substances	kinetin riboside ; Adenosine (K72T3FS567) ; Kinetin (P39Y9652YJ)
Language	English
Publishing date	2024-02-06
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45387-9
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Article ; Online: Sustained intraocular vascular endothelial growth factor neutralisation does not affect retinal and choroidal vasculature in Ins2

Lechner, Judith / Hombrebueno, Jose R / Pedrini, Edoardo / Chen, Mei / Xu, Heping

Diabetes & vascular disease research

2019 Volume 16, Issue 5, Page(s) 440–449

Abstract: The purpose of this study was to understand the influence of sustained intravitreal vascular endothelial growth factor neutralisation on the retinal and choroidal vasculature in diabetic eyes. ... ...

Abstract	The purpose of this study was to understand the influence of sustained intravitreal vascular endothelial growth factor neutralisation on the retinal and choroidal vasculature in diabetic eyes. Ins2
MeSH term(s)	Angiogenesis Inhibitors/administration & dosage ; Angiogenesis Inhibitors/toxicity ; Animals ; Antibodies, Neutralizing/administration & dosage ; Antibodies, Neutralizing/toxicity ; Choroid/blood supply ; Choroidal Neovascularization ; Diabetes Mellitus/drug therapy ; Diabetes Mellitus/genetics ; Diabetes Mellitus/metabolism ; Diabetes Mellitus/pathology ; Diabetic Retinopathy/genetics ; Diabetic Retinopathy/metabolism ; Diabetic Retinopathy/pathology ; Diabetic Retinopathy/prevention & control ; Disease Models, Animal ; Gene Expression Regulation ; Intravitreal Injections ; Male ; Mice, Inbred C57BL ; Retinal Neovascularization ; Retinal Vessels/drug effects ; Retinal Vessels/metabolism ; Retinal Vessels/pathology ; Signal Transduction ; Vascular Endothelial Growth Factor A/antagonists & inhibitors ; Vascular Endothelial Growth Factor A/genetics ; Vascular Endothelial Growth Factor A/metabolism
Chemical Substances	Angiogenesis Inhibitors ; Antibodies, Neutralizing ; Vascular Endothelial Growth Factor A ; vascular endothelial growth factor A, mouse
Language	English
Publishing date	2019-04-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2250793-0
ISSN	1752-8984 ; 1479-1641
ISSN (online)	1752-8984
ISSN	1479-1641
DOI	10.1177/1479164119843092
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Article ; Online: Hyaloid Vasculature as a Major Source of STAT3

Hombrebueno, Jose R / Lynch, Aisling / Byrne, Eimear M / Obasanmi, Gideon / Kissenpfennig, Adrien / Chen, Mei / Xu, Heping

Arteriosclerosis, thrombosis, and vascular biology

2020 Volume 40, Issue 12, Page(s) e367–e379

Abstract: Objective: Myeloid cells are critically involved in inflammation-induced angiogenesis, although their pathogenic role in the ischemic retina remains controversial. We hypothesize that myeloid cells contribute to pathogenic neovascularization in ... ...

Abstract	Objective: Myeloid cells are critically involved in inflammation-induced angiogenesis, although their pathogenic role in the ischemic retina remains controversial. We hypothesize that myeloid cells contribute to pathogenic neovascularization in retinopathy of prematurity through STAT3 (signal transducer and activator of transcription 3) activation. Approach and Results: Using the mouse model of oxygen-induced retinopathy, we show that myeloid cells (CD45 Conclusions: Circulating myeloid cells may migrate to the immature ischemic retina through the hyaloid vasculature and contribute to retinal neovascularization via activation of STAT3. Understanding how STAT3 modulates myeloid cells for vascular repair/pathology may provide novel therapeutic options in pathogenic angiogenesis.
MeSH term(s)	Animals ; Animals, Newborn ; Anthraquinones/pharmacology ; Disease Models, Animal ; Female ; Macrophages/drug effects ; Macrophages/metabolism ; Macrophages/pathology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Oxygen ; Phosphorylation ; Retinal Neovascularization/etiology ; Retinal Neovascularization/metabolism ; Retinal Neovascularization/pathology ; Retinal Neovascularization/prevention & control ; Retinal Vessels/drug effects ; Retinal Vessels/metabolism ; Retinal Vessels/pathology ; Retinopathy of Prematurity/etiology ; Retinopathy of Prematurity/metabolism ; Retinopathy of Prematurity/pathology ; Retinopathy of Prematurity/prevention & control ; STAT3 Transcription Factor/antagonists & inhibitors ; STAT3 Transcription Factor/metabolism ; Signal Transduction ; Sulfonamides/pharmacology ; Suppressor of Cytokine Signaling 3 Protein/genetics ; Suppressor of Cytokine Signaling 3 Protein/metabolism
Chemical Substances	Anthraquinones ; LLL12 compound ; STAT3 Transcription Factor ; Socs3 protein, mouse ; Stat3 protein, mouse ; Sulfonamides ; Suppressor of Cytokine Signaling 3 Protein ; Oxygen (S88TT14065)
Language	English
Publishing date	2020-10-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.120.314567
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Article ; Online: Antagonising Wnt/β-catenin signalling ameliorates lens-capsulotomy-induced retinal degeneration in a mouse model of diabetes.

Hombrebueno, Jose R / Ali, Imran H A / Ma, Jian-Xing / Chen, Mei / Xu, Heping

Diabetologia

2018 Volume 61, Issue 11, Page(s) 2433–2446

Abstract: Aims/hypothesis: Cataract surgery in diabetic individuals worsens pre-existing retinopathy and triggers the development of diabetic ocular complications, although the underlying cellular and molecular pathophysiology remains elusive. We hypothesise that ...

Abstract	Aims/hypothesis: Cataract surgery in diabetic individuals worsens pre-existing retinopathy and triggers the development of diabetic ocular complications, although the underlying cellular and molecular pathophysiology remains elusive. We hypothesise that lens surgery may exaggerate pre-existing retinal inflammation in diabetes, which may accelerate neurovascular degeneration in diabetic eyes. Methods: Male heterozygous Ins2 Results: Lens capsulotomy triggered the early onset of retinal neurodegeneration in Ins2 Conclusions/interpretation: Targeting the canonical Wnt/β-catenin signalling pathway may provide a novel approach for the postoperative management of diabetic individuals needing cataract surgery.
MeSH term(s)	Animals ; Cataract Extraction/adverse effects ; Diabetes Mellitus, Experimental/complications ; Diabetic Retinopathy/etiology ; Diabetic Retinopathy/metabolism ; Diabetic Retinopathy/pathology ; Disease Models, Animal ; Electroretinography ; Immunoblotting ; Immunohistochemistry ; Insulin/genetics ; Insulin/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Retinal Degeneration/etiology ; Retinal Degeneration/metabolism ; Retinal Degeneration/pathology
Chemical Substances	Ins2 protein, mouse ; Insulin
Language	English
Publishing date	2018-07-17
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1694-9
ISSN	1432-0428 ; 0012-186X
ISSN (online)	1432-0428
ISSN	0012-186X
DOI	10.1007/s00125-018-4682-3
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Zs.A 279: Show issues

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Article ; Online: Sustained intraocular VEGF neutralization results in retinal neurodegeneration in the Ins2(Akita) diabetic mouse.

Hombrebueno, Jose R / Ali, Imran H A / Xu, Heping / Chen, Mei

Scientific reports

2015 Volume 5, Page(s) 18316

Abstract: Current therapies that target vascular endothelial growth factor (VEGF) have become a mainstream therapy for the management of diabetic macular oedema. The treatment involves monthly repeated intravitreal injections of VEGF inhibitors. VEGF is an ... ...

Abstract	Current therapies that target vascular endothelial growth factor (VEGF) have become a mainstream therapy for the management of diabetic macular oedema. The treatment involves monthly repeated intravitreal injections of VEGF inhibitors. VEGF is an important growth factor for many retinal cells, including different types of neurons. In this study, we investigated the adverse effect of multiple intravitreal anti-VEGF injections (200 ng/μl/eye anti-mouse VEGF164, once every 2 weeks totalling 5-6 injections) to retinal neurons in Ins2(Akita) diabetic mice. Funduscopic examination revealed the development of cotton wool spot-like lesions in anti-VEGF treated Ins2(Akita) mice after 5 injections. Histological investigation showed focal swellings of retinal nerve fibres with neurofilament disruption. Furthermore, anti-VEGF-treated Ins2(Akita) mice exhibited impaired electroretinographic responses, characterized by reduced scotopic a- and b-wave and oscillatory potentials. Immunofluorescent staining revealed impairment of photoreceptors, disruptions of synaptic structures and loss of amacrine and retinal ganglion cells in anti-VEGF treated Ins2(Akita) mice. Anti-VEGF-treated WT mice also presented mild amacrine and ganglion cell death, but no overt abnormalities in photoreceptors and synaptic structures. At the vascular level, exacerbated albumin leakage was observed in anti-VEGF injected diabetic mice. Our results suggest that sustained intraocular VEGF neutralization induces retinal neurodegeneration and vascular damage in the diabetic eye.
MeSH term(s)	Animals ; Antibodies, Neutralizing/adverse effects ; Antibodies, Neutralizing/pharmacology ; Diabetes Mellitus, Experimental/drug therapy ; Diabetes Mellitus, Experimental/genetics ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology ; Diabetic Retinopathy/drug therapy ; Diabetic Retinopathy/genetics ; Diabetic Retinopathy/metabolism ; Diabetic Retinopathy/pathology ; Insulin/deficiency ; Mice ; Neurodegenerative Diseases/chemically induced ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology ; Retinal Neurons/metabolism ; Retinal Neurons/pathology ; Vascular Endothelial Growth Factor A/antagonists & inhibitors ; Vascular Endothelial Growth Factor A/metabolism
Chemical Substances	Antibodies, Neutralizing ; Ins2 protein, mouse ; Insulin ; Vascular Endothelial Growth Factor A ; vascular endothelial growth factor A, mouse
Language	English
Publishing date	2015-12-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep18316
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Article ; Online: Uncoupled turnover disrupts mitochondrial quality control in diabetic retinopathy.

Hombrebueno, Jose R / Cairns, Lauren / Dutton, Louise R / Lyons, Timothy J / Brazil, Derek P / Moynagh, Paul / Curtis, Tim M / Xu, Heping

JCI insight

2019 Volume 4, Issue 23

Abstract: Mitochondrial quality control (MQC) is crucial for regulating CNS homeostasis, and its disruption has been implicated in the pathogenesis of some of the most common neurodegenerative diseases. In healthy tissues, the maintenance of MQC depends upon an ... ...

Abstract	Mitochondrial quality control (MQC) is crucial for regulating CNS homeostasis, and its disruption has been implicated in the pathogenesis of some of the most common neurodegenerative diseases. In healthy tissues, the maintenance of MQC depends upon an exquisite balance between mitophagy (removal of damaged mitochondria by autophagy) and biogenesis (de novo synthesis of mitochondria). Here, we show that mitophagy is disrupted in diabetic retinopathy (DR) and decoupled from mitochondrial biogenesis during the progression of the disease. Diabetic retinas from human postmortem donors and experimental mice exhibit a net loss of mitochondrial contents during the early stages of the disease process. Using diabetic mitophagy-reporter mice (mitoQC-Ins2Akita) alongside pMitoTimer (a molecular clock to address mitochondrial age dynamics), we demonstrate that mitochondrial loss arose due to an inability of mitochondrial biogenesis to compensate for diabetes-exacerbated mitophagy. However, as diabetes duration increases, Pink1-dependent mitophagy deteriorates, leading to the build-up of mitochondria primed for degradation in DR. Impairment of mitophagy during prolonged diabetes is linked with the development of retinal senescence, a phenotype that blunted hyperglycemia-induced mitophagy in mitoQC primary Müller cells. Our findings suggest that normalizing mitochondrial turnover may preserve MQC and provide therapeutic options for the management of DR-associated complications.
MeSH term(s)	Animals ; Cell Line ; Diabetes Mellitus ; Diabetic Retinopathy/genetics ; Diabetic Retinopathy/metabolism ; Diabetic Retinopathy/pathology ; Disease Models, Animal ; Disease Progression ; Female ; Humans ; Insulin/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondrial Dynamics/physiology ; Mitophagy/genetics ; Mitophagy/physiology ; Protein Kinases/metabolism ; Retina/metabolism
Chemical Substances	Ins2 protein, mouse ; Insulin ; Protein Kinases (EC 2.7.-) ; PTEN-induced putative kinase (EC 2.7.11.1)
Language	English
Publishing date	2019-12-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.129760
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Article ; Online: Identification and cellular location of glutamine synthetase in human sperm.

Francou, Maria Manuela / Hombrebueno, José R / De Juan, Joaquín

Cell and tissue research

2012 Volume 350, Issue 1, Page(s) 183–187

Abstract: Glutamine synthetase (GS) catalyzes the de novo synthesis of glutamine, an amino acid that has been shown to influence sperm motility in mammals. To date, no information is available about GS content in human sperm. In this study, we have characterized ... ...

Abstract	Glutamine synthetase (GS) catalyzes the de novo synthesis of glutamine, an amino acid that has been shown to influence sperm motility in mammals. To date, no information is available about GS content in human sperm. In this study, we have characterized the presence and cellular location of GS in fresh human normozoospermic samples. We have detected a single band corresponding to GS by Western blot. Confocal analysis has revealed GS immunoreactivity in the post-acrosomal head region. Moreover, double-labeling experiments with either F-actin or calicin have demonstrated GS confinement in the post-acrosomal region of the perinuclear theca. These data have been validated by a post-embedding ultra-structural study. The presence of GS in the post-acrosomal region of the perinuclear theca suggests that human sperm can carry out in glutamine synthesis.
MeSH term(s)	Animals ; Blotting, Western ; Glutamate-Ammonia Ligase/metabolism ; Glutamate-Ammonia Ligase/ultrastructure ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Protein Transport ; Spermatozoa/cytology ; Spermatozoa/enzymology ; Spermatozoa/ultrastructure ; Tissue Extracts
Chemical Substances	Tissue Extracts ; Glutamate-Ammonia Ligase (EC 6.3.1.2)
Language	English
Publishing date	2012-10
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	125067-x
ISSN	1432-0878 ; 0302-766X
ISSN (online)	1432-0878
ISSN	0302-766X
DOI	10.1007/s00441-012-1465-x
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Article ; Online: Loss of synaptic connectivity, particularly in second order neurons is a key feature of diabetic retinal neuropathy in the Ins2Akita mouse.

Hombrebueno, Jose R / Chen, Mei / Penalva, Rosana G / Xu, Heping

PloS one

2014 Volume 9, Issue 5, Page(s) e97970

Abstract: Retinal neurodegeneration is a key component of diabetic retinopathy (DR), although the detailed neuronal damage remains ill-defined. Recent evidence suggests that in addition to amacrine and ganglion cell, diabetes may also impact on other retinal ... ...

Abstract	Retinal neurodegeneration is a key component of diabetic retinopathy (DR), although the detailed neuronal damage remains ill-defined. Recent evidence suggests that in addition to amacrine and ganglion cell, diabetes may also impact on other retinal neurons. In this study, we examined retinal degenerative changes in Ins2Akita diabetic mice. In scotopic electroretinograms (ERG), b-wave and oscillatory potentials were severely impaired in 9-month old Ins2Akita mice. Despite no obvious pathology in fundoscopic examination, optical coherence tomography (OCT) revealed a progressive thinning of the retina from 3 months onwards. Cone but not rod photoreceptor loss was observed in 3-month-old diabetic mice. Severe impairment of synaptic connectivity at the outer plexiform layer (OPL) was detected in 9-month old Ins2Akita mice. Specifically, photoreceptor presynaptic ribbons were reduced by 25% and postsynaptic boutons by 70%, although the density of horizontal, rod- and cone-bipolar cells remained similar to non-diabetic controls. Significant reductions in GABAergic and glycinergic amacrine cells and Brn3a+ retinal ganglion cells were also observed in 9-month old Ins2Akita mice. In conclusion, the Ins2Akita mouse develops cone photoreceptor degeneration and the impairment of synaptic connectivity at the OPL, predominately resulting from the loss of postsynaptic terminal boutons. Our findings suggest that the Ins2Akita mouse is a good model to study diabetic retinal neuropathy.
MeSH term(s)	Animals ; Diabetes Mellitus, Type 1/complications ; Diabetic Retinopathy/complications ; Diabetic Retinopathy/pathology ; Electroretinography ; Male ; Mice ; Retinal Neurons/pathology ; Synapses/pathology ; Time Factors
Language	English
Publishing date	2014-05-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0097970
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Article ; Online: ECSIT is a critical limiting factor for cardiac function.

Xu, Linan / Humphries, Fiachra / Delagic, Nezira / Wang, Bingwei / Holland, Ashling / Edgar, Kevin S / Hombrebueno, Jose R / Stolz, Donna Beer / Oleszycka, Ewa / Rodgers, Aoife M / Glezeva, Nadezhda / McDonald, Kenneth / Watson, Chris J / Ledwidge, Mark T / Ingram, Rebecca J / Grieve, David J / Moynagh, Paul N

JCI insight

2021 Volume 6, Issue 12

Abstract: Evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) is a protein with roles in early development, activation of the transcription factor NF-κB, and production of mitochondrial reactive oxygen species (mROS) that facilitates clearance ...

Abstract	Evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) is a protein with roles in early development, activation of the transcription factor NF-κB, and production of mitochondrial reactive oxygen species (mROS) that facilitates clearance of intracellular bacteria like Salmonella. ECSIT is also an important assembly factor for mitochondrial complex I. Unlike the murine form of Ecsit (mEcsit), we demonstrate here that human ECSIT (hECSIT) is highly labile. To explore whether the instability of hECSIT affects functions previously ascribed to its murine counterpart, we created a potentially novel transgenic mouse in which the murine Ecsit gene is replaced by the human ECSIT gene. The humanized mouse has low levels of hECSIT protein, in keeping with its intrinsic instability. Whereas low-level expression of hECSIT was capable of fully compensating for mEcsit in its roles in early development and activation of the NF-κB pathway, macrophages from humanized mice showed impaired clearance of Salmonella that was associated with reduced production of mROS. Notably, severe cardiac hypertrophy was manifested in aging humanized mice, leading to premature death. The cellular and molecular basis of this phenotype was delineated by showing that low levels of human ECSIT protein led to a marked reduction in assembly and activity of mitochondrial complex I with impaired oxidative phosphorylation and reduced production of ATP. Cardiac tissue from humanized hECSIT mice also showed reduced mitochondrial fusion and more fission but impaired clearance of fragmented mitochondria. A cardiomyocyte-intrinsic role for Ecsit in mitochondrial function and cardioprotection is also demonstrated. We also show that cardiac fibrosis and damage in humans correlated with low expression of human ECSIT. In summary, our findings identify a role for ECSIT in cardioprotection, while generating a valuable experimental model to study mitochondrial dysfunction and cardiac pathophysiology.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Cardiomegaly/metabolism ; Cardiomegaly/pathology ; Cells, Cultured ; Humans ; Macrophages/metabolism ; Mice ; Mitochondria/metabolism ; Myocardium/metabolism ; Myocardium/pathology ; NF-kappa B/genetics ; NF-kappa B/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; ECSIT protein, mouse ; Ecsit protein, human ; NF-kappa B
Language	English
Publishing date	2021-06-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.142801
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